Abstract
Objective:
To characterize the molecules and the mechanisms regulating the neoangiogenetic process in advanced atherosclerotic plaques.
Methods and results:
Western blot and immunofluorescence analysis of atherosclerotic specimens demonstrated that unlike neovessels from early lesions that expressed vascular endothelial growth factor (VEGF) and angiopoietin1 (Angio1), vessels from advanced lesions expressed VEGF and angiopoietin 2 (Angio2). Moreover, only few neovessels from advanced lesions showed a positive immunostaining for proliferating cell nuclear antigen. Angio1-elicited and Angio2-elicited intracellular events in endothelial cells (EC) demonstrated that while Angio1 triggered Erk1/Erk2 mitogen activated protein kinases (MAPK) and Akt activation, Angio2 (50 ng/mL) induced STAT5 activation and p21waf expression and increased the fraction of cells in G1. Both Angio2-mediated events were abrogated by expressing a dominant negative STAT5 construct (DeltaSTAT5). Consistent with the expression of Angio2 in neovessels of advanced lesions a transcriptionally active STAT5 was detected. Moreover, co-immunoprecipitation experiments revealed the presence of a STAT5/Tie2 molecular complex in neointima vessels from advanced, but not from early, lesions.
Conclusions:
In advanced lesions, the activation of the Tie2-mediated STAT5 signaling pathway may negatively regulate vessel growth.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiopoietin-1 / biosynthesis
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Angiopoietin-1 / genetics
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Angiopoietin-1 / physiology
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Angiopoietin-2 / biosynthesis
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Angiopoietin-2 / genetics
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Angiopoietin-2 / pharmacology
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Angiopoietin-2 / physiology*
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Arteriosclerosis / pathology*
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Carotid Arteries / metabolism
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Carotid Arteries / pathology
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Carotid Artery Diseases / pathology
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Cell Cycle / drug effects*
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Cell Cycle Proteins / biosynthesis
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Cell Cycle Proteins / genetics
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Cell Line, Tumor / metabolism
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Cells, Cultured / drug effects
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Cells, Cultured / metabolism
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Coronary Artery Disease / pathology
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Coronary Vessels / metabolism
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Coronary Vessels / pathology
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins / genetics
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DNA-Binding Proteins / physiology*
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Disease Progression
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Endothelial Cells / cytology
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Endothelial Cells / drug effects*
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Endothelium, Vascular / pathology
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G1 Phase / drug effects
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Gene Expression Regulation / drug effects
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Gene Expression Regulation / physiology
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Humans
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Macromolecular Substances
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Milk Proteins / genetics
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Neovascularization, Physiologic / drug effects
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Neovascularization, Physiologic / physiology
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Proliferating Cell Nuclear Antigen / biosynthesis
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Proliferating Cell Nuclear Antigen / genetics
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Receptor, TIE-2 / physiology*
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STAT5 Transcription Factor
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Signal Transduction / drug effects
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Trans-Activators / genetics
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Trans-Activators / physiology*
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Transcription, Genetic
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Transfection
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Tunica Intima / pathology
Substances
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Angiopoietin-1
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Angiopoietin-2
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CDKN1A protein, human
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Cell Cycle Proteins
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Cyclin-Dependent Kinase Inhibitor p21
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DNA-Binding Proteins
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Macromolecular Substances
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Milk Proteins
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Proliferating Cell Nuclear Antigen
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STAT5 Transcription Factor
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Trans-Activators
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Receptor, TIE-2